US Scientists Demand Removal Of Restrictions On Animal Chimera Research

The US National Institutes of Health has stopped funding experiments in which human stem cells are transplanted into the embryo of an animal. Now, a group of researchers from Stanford University are speaking out, claiming that the restrictions are holding back important medical research — and that the NIH's reasons aren't backed by science.

Late last month, the NIH issued a notice stating that it "will not fund research in which human pluripotent cells are introduced into non-human vertebrate animal pre-gastrulation stage embryos while the agency considers a possible policy revision in this area." More simply, the NIH worries that "chimeric research," in which animal traits are generated with tissues derived from human stem cells, could be harmful to those animals. In an accompanying letter, "Staying Ahead of the Curve on Chimeras," the NIH's Carrie D. Wolinetz explained:

As described in the Guide notice, this is an exciting area of science that is rapidly progressing, but in which ethical and animal welfare considerations might merit additional guidance to move forward. This is a unique opportunity to take a deep breath, look at the state of the science, and think about current policies and consider whether any additional policies are needed to promote the responsible conduct of this promising science.

Advocates of the practice claim that chimeric research could lead to a host of powerful medical advances. What's more, they claim that the NIH's objections are completely without warrant.

"We believe that human/non-human chimerism studies hold tremendous potential to improve our understanding of early development, enhance disease modelling, and promote therapeutic discovery," write the group of Stanford scientists and bioethicists in an open Science letter. "The recently announced funding restriction by NIH serves to impede scientific progress in regenerative medicine and should be lifted."

No doubt, the ability to emulate human characteristics within an animal model — including diseases like sickle cell anemia and various organ deficiencies — is a powerful idea. But the NIH is worried that the introduction of human stem cells into nonhuman embryos may result in the formation of human neurons in animal brain, and the emergence of human germ cells, i.e. sperm and egg, in the gonad of the chimeric animals. The fear is that these animals might have human-like brains and thought-processes, and that animals carrying human germ cells might reproduce and create a kind of hybrid animal that's partly human-like.

But as letter co-author and Assistant Professor of Medicine Sean M. Wu explained to Gizmodo, this is a concern without foundation.

"The potential for human neurons in a host animal to make the animal think and feel like human has been imagined but not supported by any scientific evidence so far," he said. "Currently, the number of human cells that can be integrated into an animal embryo is extremely small that if any human stem cell can survive and develop into a human neuron in an animal embryo, it would contribute to no more than a few per cent of all the neurons in that animal at best which is extremely unlikely to make that animal think like a human."

Indeed, the idea that a chimeric mouse, endowed with a small sample of human cells, might start to exhibit human-like intelligence and awareness seems grossly implausible. The authors articulate this concern quite cogently in their letter:

Much of the bioethical concern in regards to human/non-human chimerism arises from the possibility of chimeric animals harboring human neurons and germ cells. Can human neural cells co-exist with those from animals and establish "humanized" cerebral anatomy and circuitries? Furthermore, would such chimeras be elevated to a higher metaphysical state and "think" more like us? Current scientific data have not supported such possibilities, despite hundreds of xenotransplant studies introducing human neurons into the mouse brain.

As for the concern about germ cells and human-animal hybrid offspring, Wu said that this "scenario is also quite far fetched." It's also a moot point because the National Academy of Medicine has already recommended against breeding any animal that could be carrying human germ cells.

"Hence, the new restriction that was recently announced by the National Institutes of Health appears to represent efforts to prevent scientists from even considering these experiments that have not demonstrated any potential for harm," Wu said.

Along with Stanford scientists and letter signatories Irving L. Weissman, Arun Sharma, Vittorio Sebastiano, and others, Wu feels that the restrictions are impeding our ability to understand how human stems cells can develop into cells that produce different organs and tissue in a living individual. Because it isn't ethical to experiment on early stage human embryos, this process — in which human stem cells are placed into an early stage animal embryo — is the next closest thing.

"The understanding that we gain from these studies can then help us replicate these steps in the dish so that we can create those tissues for therapy using human stem cells," said Wu. "In addition, there has been early hints from researchers that when a special type of stem cell is placed in the early embryo from the same or similar animal species that is modified to be unable to form a specific organ such as pancreas, kidney, or heart, the stem cell that is introduced can compensate to help regrow the entire organ in the host animal."

On this topic — that of animal experimentation — I asked Wu if there aren't any viable alternatives to chimeric research.

"The early stage embryo is the best, if not only, environment that can guide and coach the special human stem cell to appropriately differentiate into various different cell types with the right geometry," he replied. "There is no other alternative right now or in the foreseeable future that can replicate all of the complexities of early stage embryo development than in an embryo itself."

I contacted the NIH and asked if they had a response to the Stanford letter. Here's their response to Gizmodo in full:

Research using animal models containing human cells is certainly not new. The identification of different types of human stem cells, such as hematopoetic stem cells, involved introducing the human cells into mice to validate the identity of the human cells and study their property. However, research in which human pluripotent cells are introduced into non-human vertebrate animal pre-gastrulation stage embryos is an area of some concern, given the possibility of human cell contribution to multiple organs and tissues. A significant contribution of human cells in an animal, if that were to occur, may raise concerns for the welfare of the animal, particularly if there are significant alterations of the animal's cognitive state. Part of the focus of this workshop is to gain a better understanding of the scientific possibilities.

NIH intends to undertake a deliberative process to review the state of the science, re-examine current NIH policies and procedures related to this type of research, and contemplate whether new policies and procedures are needed to ensure this research can progress responsibly. Therefore, this policy will be in place until NIH issues a subsequent policy notification. By taking a proactive approach to policy development before the research gets ahead of us — that is, attempting to foresee where the science is taking us — we can try to make sure that our policies provide a prudent path forward so that important research is facilitated, not impeded, by a sound policy framework.

Moving forward, the Stanford researchers are hoping to receive an explanation from the NIH in regards to the rationale for the funding restriction. Should that explanation not make any scientific sense based on the available evidence, they will formally request that the funding restriction be removed so that, in Wu's words, "experiments along this line of research can be proposed for funding and be funded by the NIH if they are reviewed favourably by an independent panel of scientists."

Top image by Shutterstock.

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